Abstract Non-infectious autoimmune uveitis is a sight-threatening inflammatory eye disease which accounts for 10% of preventable blindness, despite currently available therapies. There is a high demand for medications which not only provide anti-inflammatory efficacy but are well tolerated by the patient. Cannabinoid (CBD) is one of the major components of marijuana without psychotropic effects. It is being explored for treating a number of pathological conditions in animal models and in patients, including cancer, inflammatory diseases, neuro-degenerative diseases, substance abuse disorders, etc. Currently, evidence supports CBD as an immune-modulating agent, affecting T cells, B cells, monocytes and microglia cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. However, CBD has not been studied in animal models of autoimmune uveitis or the patients with uveitis. G protein-coupled receptor 3 (GPR3) belongs to a family of closely related orphan receptors. Although it has been reported to play important roles in many normal physiological functions and be involved in a variety of pathological conditions, until recently we found that CBD is an inverse ligand for GPR3. This discovery highlights this orphan receptor as a potential new molecular target for CBD with a novel mechanism of CBD action. In our pilot study, we discovered that GPR3 is expressed at low levels in the spleen, and barely detectable in the eye in nave mice. The expression, however, is dramatically increased during intraocular inflammation. Further, we identified that T cells and antigen presenting cells (APCs) of B cells, and dendritic cells (DCs) express GPR3. The role of GPR3 on these cells is unknown. It is also unknown whether CBD produces GPR3-mediated therapeutic effects in EAU. In this application, we will use our well-established T cell-mediated experimental autoimmune uveitis (EAU) models to test the potential therapeutic effects of CBD on EAU (Aim 1), and the functional impact of GPR3 on EAU development (Aim 2), and whether the therapeutic effects of CBD on EAU is mediated by GPR3 in vivo and in vitro (Aim 3) These studies will provide a preclinical proof for CBD as a potent anti-inflammatory, photoreceptor protective and analgesic drug for patients with uveitis and advance our understanding of CBD ?GPR3 interaction in the development of autoimmune uveitis.